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EDITORIALS |
From the John Wayne Cancer Institute, Santa Monica, California.
Correspondence: Address correspondence to: Armando Giuliano, MD, Director, Joyce Eisenberg Keefes Breast Cancer Center at the John Wayne Cancer Institute, 2200 Santa Monica Blvd., Santa Monica, CA 90404; Fax: 310-998-3995; E-mail: giulianoa{at}jwci.org
The surgical management of breast cancer has evolved from radical ablative procedures to breast conservation as the preferred method of treatment for early-stage disease. Identification of axillary lymph node metastases is currently a topic of intense investigation and redefinition. Although lymph node metastasis remains the single most important prognostic factor, axillary lymph node dissection (ALND) is of uncertain value in an increasingly larger number of women without clinical lymph node involvement. Sentinel lymph node (SLN) dissection has evolved as an accurate, less invasive assessment of the axilla1–3 and is rapidly developing into standard practice despite a lack of uniform technical details and definitions.
In this issue of Annals of Surgical Oncology, Cody et al.4 and Boolbol et al.5 at Memorial Sloan-Kettering Cancer Center (MSKCC) report their approach and extensive experience with lymphatic mapping and SLN dissection using the dual techniques of blue dye and radioisotope injection. They detail the factors that have contributed to their success and provide a statistical analysis of the most important prognostic factors for this success. This group has been one of the strongest proponents of the dual method of SLN identification as reported by Albertini et al.3 and has accumulated an enormous experience, which they report in this issue.
Boolbol et al.5 present the latest evolution of the dual-indicator method at their institution. Their present study was designed to assess the accuracy and false-negative rate of the combined use of intradermal radioisotope and intraparenchymal blue-dye injection in 101 patients who underwent SLN dissection and planned ALND. Blue dye injected into the peritumoral breast parenchyma successfully identified a SLN in 85% of the procedures. Intradermal injection of radioisotope produced a 93% success rate, which is similar but lower than previously reported by Linehan et al.6 from their own institution. The success rate of the dual method to identify a hot and/or blue SLN was 99% with an overall accuracy of 96%. Forty-six percent of the axillae were positive, compared to 26.4% in the cumulative MSKCC experience described by Cody et al.4 Does technique matter? Or do other confounding variables account for this disparity? There were four false-negative cases. Three of the four had intraoperatively palpable suspicious nodes at the time of exploration. The authors postulate that in cases of grossly involved nodes the lymph flow to the tumor-containing node may be obstructed. This may be an accurate conclusion and has been observed by others,7 or it may actually represent an error in technique in these cases. The authors conclude that intradermal injection of isotope is highly accurate and preferable to intraparenchymal injection, but have not tested each technique independently. In fact, staging of the axilla by extrapolating from the intradermal injection data was successful in 93% of the procedures and localized only 40 of the 46 positive axillae, a 13% false-negative rate. Disturbingly, lymphoscintigraphy failed to show internal mammary drainage, which would be expected in some cases of breast cancer, but less commonly in cutaneous melanoma. One recent study reported visualization of internal mammary lymph nodes only after intraparenchymal peritumoral isotope injection, not intradermal injection, suggesting that the two routes of injection are not identical.8
In the accompanying article by Cody et al.,4 the cumulative experience of seven surgeons treating 1000 consecutive patients at a single institution analyzes the most significant variables that contribute to the success of SLN mapping in 966 detailed cases. In Table 1, the cumulative success rate of each technique is shown for 966 procedures. The authors report a success rate of 81% for blue dye, 87% for isotope, and 95% for the combined procedure, leading them to the recommendation that a combined approach is complementary and optimal. While it is true that identification of a SLN in both the studies reported in this issue is higher when the total number of nodes identified by blue, hot, and both is summated, one could raise the possibility that when combining the two techniques neither is optimized. The success of each method alone in both studies falls below our own experience with blue dye alone and that of others using isotope alone. We have reported a success rate of 94% and an accuracy rate of 100%.9 In over 300 consecutive cases with blue dye alone, there have been no failures to identify the SLN. This difference may be explained by differences in our blue dye technique. The MSKCC authors inject 1 to 5 ml isosulfan blue approximately 10 minutes before skin incision and perform tumor excision prior to axillary exploration and SLN dissection. In contrast, 5 ml of isosulfan blue and 5 minutes of breast massage followed by lymphatic mapping prior to breast resection produce consistent results in our hands. At times for very high upper outer quadrant lesions, 3 ml is sufficient. One ml never worked when we were developing the technique. Radioisotope SLN localization in their hands is also less than that of Veronesi et al.10 who achieved a success rate of 98.7% with an accuracy of 95.5%. A recent study that looked at learning of SLN dissection did compare the blue dye technique alone to blue dye plus radioactivity and concluded that there was no advantage to the addition of radioisotope.11 In addition, these authors posed several important drawbacks to the use of radioactivity including cost for equipment and radiocolloid and inconvenience to both patient and surgeon.
Cody et al.4 compare and contrast those prognostic variables important for lymphatic mapping for blue dye and radioisotope. Their study is based on the hypothesis that the success of SLN mapping is optimized by the combined method, which may not be correct. These findings are considered valid only in the context of dye and isotope injection. It must be emphasized that this study using the dual method was not designed to compare blue dye alone to radioisotope alone; therefore any prognostic assessment is applicable only for simultaneous injection of dye and isotope. The strength of this study lies in the magnitude of experience and the statistical power. The weakness is that this is a cumulative experience with techniques in evolution and the use of a combined approach not validating each individual technique separately. All patients who had lymphatic mapping using a variety of techniques, including filtered versus unfiltered isotope and intraparenchymal versus intradermal isotope injection, were included in the analysis. The authors themselves raise the caveat that the results of each method may to some extent influence the other.
Some of the prognostic factors that predict the success for each indicator method are shared, and others are unique. A positive lymphoscintigram (LSG), outer quadrant tumor, previous surgical biopsy, and age <60 were significant for blue dye in univariate analysis. In multivariate analysis, previous surgical biopsy was irrelevant for blue dye. Positive LSG, intradermal injection of isotope, and age <60 were significant in univariate and multivariate analysis for isotope alone and for the dual method. The authors point out that a positive LSG is of no surprise for localization by isotope but is somewhat less intuitive for blue dye, and they suggest that this may lead to the discovery of a blue node which might have not otherwise been found. Alternatively, the LSG may be prognostic for both indicators because it demonstrates equal uptake of either agent by the SLN when there is no lymphatic stasis. A positive LSG was observed in only 50% of the cases. In those cases, could it have made the surgeon more vigilant at finding the SLNs in a particular location? Because the incidence of positive LSG is low in the study, is it worth doing? Rahusen et al.7 report a 91% ability to identify a clear focal axillary hot spot on preoperative LSG and recommend the triple technique of preoperative LSG, the gamma probe, and blue dye for a high success rate of the SLN procedure. The details of axillary status with respect to LSG would be of some interest in view of the incidence of negative LSG in three of four false-negative SLN in the accompanying paper. Age <60 is a strong predictor for successful lymphatic mapping and is under investigation by the authors. Morrow et al.11 recognized that SLN identification was more likely to fail in older patients. Blue dye was more successful at localizing lateral tumors. Most tumors are lateral. Intradermal radioisotope injection was more successful than intraparenchymal injection. There is less shine-through with intradermal radioisotope in the outer quadrants, but blue dye was better in their study for this location. The authors state that intradermal isotope injection remains the single technical modification that has the most influence on successful SLN localization. However, this study from Cody’s group was not designed to compare the blue dye to radioisotope and the conclusions are only valid for the use of both modalities, nor was it designed to compare injection techniques. In a recent study, a stepwise logistic regression analysis of prognostic factors identified the number of cases done by an individual surgeon, tumor location, needle localization, and body mass index as significant predictors, but there was no prognostic advantage for the addition of radioactivity to blue dye alone.11 New ways will evolve as we have a greater understanding of the tools and the prognostic factors important for success. Intradermal injection technique may be an improvement, but the results of their study do not prove that.
One matter of concern raised by both the Boolbol et al.5 and Cody et al.4 studies is the issue of targeting concordance of the SLN using radioisotope and blue dye. As seen in Table 1 of Cody et al., there is a 5% failure rate, a 73% targeting concordance of an identical blue and hot SLN, and a 22% targeting discordance identifying hot only in 14% and blue only in 8%. Boobol et al. also demonstrated a blue-hot SLN matching concordance of 78% with 22% discordance accounted for by 15% for a hot SLN and 7% for a blue SLN. This mismatch in lymphatic mapping and radiolocalization is not well addressed in either study. If, as the authors propose, the lymphatic drainage of the dermis and breast parenchyma is the same, should there not be a better targeting concordance as is demonstrated by others who employ a variation of the dual-marker technique to locate an identical blue-hot SLN in 94% of the successful axillary mapping procedures?7,12 One might anticipate a higher concordance with greater experience of a technique if there were no confounding factors.
The opportunity to avoid ALND or to improve staging through molecular assessment of the SLN depends on the ability to localize the SLN and the accuracy of SLN to reflect the status of the axilla. There are three current national prospective trials to evaluate SLN mapping with standardized criteria, one from the NSABP and two from the American College of Surgeons. These three protocols have evolved from extensive feasibility studies for successful SLN identification which have confirmed the accuracy of the SLN as representative of the status of the axilla. In the absence of participation in these trials, each institution must set up a program with strict technical guidelines suitable for its community and confirm feasibility and accuracy. Although the accuracy of the SLN to predict the status of the nodal basin is high (95–100%) with the blue, hot, or combined techniques, they fail to localize the SLN in 3% to 35% of cases.13 Explanations for the observed differences include variations in methodology such as: radioactive and/or color indicator, timing of surgery after injection, site of injection (peritumoral, subdermal, intradermal, subareolar), particle size of isotope, type of carrier molecule (99mTc-sulfur colloid, 99mTc-human serum albumin or 99mTc-antimony colloid), dose of isotope (5–60 MBq), stringency criteria for ex vivo SLN counts to postexcision axillary bed counts, type of vital dye (Lymphazurin or patent blue-V), method of pathological examination, surgical learning curve, and case-load volume.13,14 There are many variables. It is important to understand the variations and subtleties of these techniques, maintain standardized methodology, and approach SLN mapping with the degree of stringency exemplified by the authors. Considerable discussion and publication of anecdotal series are addressing which technique is better, easier to learn, and more accurate. These seem to miss the point both in design and intent. What is important is not what agents or technique were used, but that it is validated at each institution. The various techniques can be done by those who are experienced in them. Regardless of which technique is used, each surgeon must perform a systematic analysis of a model and proficiency testing of the multidisciplinary team responsible for the detection and processing of the SLN for successful and accurate assessment of the axilla. The surgeons at MSKCC have developed an extraordinary expertise with the dual technique of SLN localization and have achieved a high degree of success. Their work helps us understand factors that contribute to success and raises important issues concerning isotope injection technique. Although the technique produces accurate results in their hands, it must still be confirmed locally wherever it is adopted. It is important to keep this in mind. What has been successful in New York must be validated in Poughkeepsie.
Received for publication October 30, 2000. Accepted for publication November 1, 2000.
REFERENCES
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